Response to Bell and Brunzell

In his commentary, Bell (1) presents specific criticisms of the head-to-head trial comparing the effects of rosiglitazone with pioglitazone on lipids and lipoproteins. Bell raises a concern over study recruitment (in particular the high rate of screen failures), the exclusion of patients on statin therapy, and the limited data supporting the role of hypertriglyceridemia in cardiovascular risk. By excluding patients on other glucose- and lipid-lowering medication, we were able to demonstrate that the two agents have different effects on each of the components of the lipid profile. In doing so, the differences observed could only be attributed to the active thiazolidinedione (TZD) therapy. Targets for LDL cholesterol were lowered during the active phase of this trial. Given that, recruitment of appropriate subjects was challenging. Although this population does not currently represent the standard of practice, the study as performed allowed careful assessment of the isolated drug effect of each TZD on lipids.

Unfortunately, Bell and others have misrepresented the two prior studies of the add-on effect of statin (2) or statin + ezetemibe (3) therapy to TZD. First, this subanalysis of LDL cholesterol (not lipid profiles as stated by Bell) was over a wide range of doses of the nonrandomized TZD treatments and, unlike our study, was substantially underpowered to compare differences in lipid parameters between agents. Furthermore, only change from baseline (without baseline and end point) LDL cholesterol results were presented in the studies. Therefore, contrary to Bell’s assertion, baseline differences (as anticipated from our data and others [4]) would be expected to be preserved at end point since changes from baseline were similar for the two TZDs. To conclude that there are no differences between the TZD effects on lipids in statin-treated patients without any data is therefore questionable. More recently, the results of the COMPLEMENT study were reported (5) confirming that the difference in the effect of the two TZDs persisted in over 305 subjects on statin therapy.

The role of triglycerides in determining cardiovascular disease risk remains controversial, and we did not evaluate postprandial lipemia in our study. No head-to-head comparative study has been performed assessing the differential impact of the two TZDs on postprandial lipids. In response to Bell’s and Brunzell’s (6) request for data on HDL subclasses, we have reported that both HDL size and large HDL cholesterol increased with pioglitazone and decreased with rosiglitazone (7), and a detailed analysis of the results of lipoprotein particle analysis on LDL, VLDL, and HDL is currently underway.

Lastly, we used a standard definition of “completers” in our patient flow diagram: all patients who completed the full 24 weeks of active therapy. The numbers of patients exposed to the full dose of each active therapy were very similar (323 for pioglitazone and 314 for rosiglitazone). The data presented in Fig. 2 of the report along with the last-observation-carried-forward analysis P value (Table 2) clearly refutes Brunzell’s speculations and underscores the absolute robustness of our data and conclusions (8).

In summary, currently available data clearly demonstrate more favorable effects of pioglitazone on plasma lipids and lipoproteins compared with rosiglitazone (lowering triglycerides, raising HDL to a greater extent, and not increasing non-HDL cholesterol and apolipoprotein B levels or LDL particle concentration). These differences may be associated with long-term vasculoprotective advantages.

Footnotes

D.M.K. has received grant support from Amylin Pharmaceuticals and Eli Lilly. M.A.D. has received honoraria from Takeda Pharmaceuticals.